1-Bromo-3,5-bis(trifluoromethyl)benzene → Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate

HRID 604151Notes

Reaction equation

HRID 604151 reaction equation
C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH:43]([C:46]1[CH:47]=[CH:48][C:49]([O:81][CH3:82])=[C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=2[CH2:62][NH:63][C:64]2[N:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:66][N:65]=2)[CH:51]=1)([CH3:45])[CH3:44].Br[C:84]1[CH:89]=[C:88]([C:90]([F:93])([F:92])[F:91])[CH:87]=[C:86]([C:94]([F:97])([F:96])[F:95])[CH:85]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:91][C:90]([F:92])([F:93])[C:88]1[CH:89]=[C:84]([N:63]([CH2:62][C:53]2[CH:54]=[C:55]([C:58]([F:61])([F:59])[F:60])[CH:56]=[CH:57][C:52]=2[C:50]2[CH:51]=[C:46]([CH:43]([CH3:45])[CH3:44])[CH:47]=[CH:48][C:49]=2[O:81][CH3:82])[C:64]2[N:65]=[CH:66][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:68][N:69]=2)[CH:85]=[C:86]([C:94]([F:95])([F:96])[F:97])[CH:87]=1

Participants

6

Reactant 3

HCID 676021-Bromo-3,5-bis(trifluoromethyl)benzeneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 66603218Tert-butyl 4-{2-[(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate

Product 1

HCID 86626893Tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrateYield 74%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent2×

Procedure

To toluene (1 ml) are added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg) and palladium acetate (II) (16 mg) and the mixture is stirred under nitrogen atmosphere at room temperature for 5 minutes. To the mixed solvent is added the mixed solution of tert-butyl 4-{2-[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg), 1-bromo-3,5-bis-trifluoromethyl-benzene (126 mg) and toluene (1.5 ml), and the mixture is degassed under reduced pressure and thereto is added sodium tert-butoxide (51 mg) and the mixture is stirred under nitrogen flow at 80° C. overnight. The reaction solution is allowed to cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=10:1) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (204 mg). MS (m/z): 772 [M+H]+

Workup

  1. customthe mixture is degassed under reduced pressure
  2. additionis added sodium tert-butoxide (51 mg)
  3. stirringthe mixture is stirred under nitrogen flow at 80° C. overnight
  4. temperatureto cool to room temperature
  5. additionis added a saturated brine
  6. extractionthe mixture is extracted with ethyl acetate
  7. washthe organic layer is washed with a saturated brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=10:1)

Sources & evidence

ORD record
ord-bf468381ab6e4f43af1de3399e2c4993
Source dataset
uspto-grants-2011_03
Patent number
US07906517B2

Reaction notes

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